The mainstay of treatment for advanced prostate cancer is androgen deprivation therapy, but most prostate cancers that initially respond to treatment ultimately become castration resistant and recur. The focus of this K99/R00 proposal is on understanding how prostate stem/progenitor cells and tumor propagating cells are affected by androgen deprivation. Previous studies from the Shen lab have identified a Nkx3.1 expressing luminal stem cell population (CARNs) in the normal regressed adult mouse prostate that can act as a cell of origin for prostate cancer. New preliminary data suggests that CARNs can also be found in the developing prostate, which is an environment with limited circulating androgens, and thus an ideal system to study castration resistance and the differentiation potential and plasticity of prostate cells. This application is based on the central hypothesis tht luminal stem cells in normal developing prostates have a predetermined ability to survive androgen deprivation, and that prostate cancers also contain tumor propagating cells with preexisting resistance to androgen deprivation. I propose to investigate the properties of stem cells and tumor propagating cells using genetic lineage tracing and ex vivo culture approaches with the following specific aims: (1) Analysis of prostate progenitor cells in the absence of androgen signaling (K99 phase), (2) Analysis of tumor propagating cells in prostate tumors and their response to androgen deprivation (K99 and R00 phases), and (3) Investigation of molecular drivers of tumor propagation in castration resistant prostate cancer (R00 phase). These studies are designed to expand our understanding of the differences and similarities between castration resistant stem cells in normal prostates and in tumors, and provide insights into the molecular mechanisms controlling intrinsic resistance to androgen deprivation. Such information will be important for understanding why hormone deprivation therapies fail, and for developing better treatments for castration resistant prostate cancers. If successful, these studies could lead to the identification of new mechanisms for castration resistance that could be translated to biomarkers for distinguishing indolent and aggressive prostate cancers and prostate cancer treatments. My long-term career goal is to establish an independent laboratory at an academic institution and conduct basic scientific research to address fundamental questions related to stem cells and cellular differentiation in cancer initiation and recurrence. M immediate goal is to develop a competitive independent research program and gain additional cancer research and translational research experience. My proposed studies of novel genes and pathways involved in tumor propagation in castration resistant prostate cancer should allow me to distinguish myself from my mentor.